Polymorphic form of rimonabant method for preparing it and pharmaceutical compositions containing it

ABSTRACT

The present invention relates to a novel crystalline polymorph of rimonabant, its method of preparation and the pharmaceutical compositions containing this novel polymorph.

The present invention relates to a novel polymorph ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamideand a method for its preparation. More particularly the inventionrelates to the preparation of this polymorph called form II and topharmaceutical compositions containing it.

N-Piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamidewhose international nonproprietary name is rimonabant is an antagonistof the CB₁ cannabinoid receptors, which was described for the first timein European patent EP 0 656 354. The method claimed in this patentallows the preparation of rimonabant in crystalline form which will becalled form I. It has now been found that rimonabant can exist invarious polymorphic crystalline forms which differ from each other intheir stability, in their physical properties, in their spectralcharacteristics and in their method of preparation.

Thus, the subject of the present invention is a novel polymorphic formof rimonabant, called form II, it also relates to methods for preparingrimonabant in its polymorphic form II, and pharmaceutical compositionscontaining the said form II.

European patent EP 0 656 354 makes no reference to the existence ofspecific polymorphic forms of rimonabant. In this patent, it isdisclosed that the compound is isolated according to conventionaltechniques; more precisely, according to the embodiments exemplified,the product is obtained after crystallization from isopropyl ether or bycooling of a medium containing the product in methylcyclohexane.

It has now been found that by using particular crystallizationconditions, a novel stable crystalline form called form II is obtained.

The crystalline form II of rimonabant has been characterized andcompared to the crystalline form I previously described.

The infrared (I.R.) spectra of the 2 crystalline forms of rimonabanthave been recorded on Perkin Elmer System 2000 FT-IR spectrophotometers,between 400 cm⁻¹ and 4 000 cm⁻¹, with a resolution of 4 cm⁻¹, in apotassium bromide pellet, the test compound being at the concentrationof 0.5% by mass.

These spectra are characterized by the absorption bands presented in thefollowing Tables 1 and 2. TABLE 1 I.R. spectrum, form I λ (cm⁻¹) 3265.531667.78 901.57 761.61

TABLE 2 I.R. spectrum, form II λ (cm⁻¹) λ (cm⁻¹) 3311.30 1484.80 2787.23986.57 1683.48 922.58 1526.55 781.02

The corresponding spectra are reproduced in FIGS. 1 and 2.

The X-ray (XR) powder diffractograms for the crystalline forms I and IIwere recorded. The X-ray powder diffraction profile (diffraction angle)was established with a Siemens D500TT (theta/theta), Bragg-Brentanotype, diffractometer; CuKα₁ source, λ=1.5406 Å; scanning range 2° to 40°at 1° per minute in Bragg 2 theta.

The characteristic lines of the diffractograms of the 2 compounds arepresented in the following tables: TABLE 3 Powder X-rays, form I PeakAngle ångstroms 2-Theta° d = 9.65570 9.151 d = 7.58833 11.652 d =7.17682 12.323 d = 5.51204 16.067 d = 5.38190 16.458 d = 5.25349 16.863d = 4.82130 18.387 d = 4.56563 19.426 d = 4.28517 20.712 d = 4.1686021.297 d = 3.87660 22.922 d = 3.27222 27.231

TABLE 4 Powder X-ray, form II Peak Angle ångstroms 2-Theta° d = 17.416645.070 d = 8.70963 10.148 d = 8.19062 10.793 d = 5.82785 15.191 d =4.63425 19.136 d = 3.49212 25.486

The corresponding diffractograms are reproduced in FIGS. 3 and 4.Rimonabant crystalline form II is also characterized by its crystalstructure for which the lattice parameters were determined bysingle-crystal X-ray diffraction. TABLE 5 Lattice parameter, form IIMolecular formula Cl3N4OC22H21 Molecular weight 463.78 Lattice structuremonoclinic Space group P 21/c Symmetry elements ‘x, y, z’ ‘−x, y + ½,−z + ½’ ‘−x, −y, −z’ ‘x, −y − ½, z − 1/ Lattice parameter a 17.4670 (7)Å Lattice parameter b 9.2820 (9) Å Lattice parameter c 13.9450 (14) ÅLattice parameter α 90.00° Lattice parameter β 91.994 (5)° Latticeparameter γ 90.00° Lattice volume 2259.5 (3) Å3 Number of molecules percell: Z 4

From the rimonabant single-crystal form II, a simulated powderdiffractogram (theoretical diffractogram) was obtained which wascompared with that obtained experimentally. FIG. 5 shows the comparisonof the diffractograms obtained.

The very high similarity observed indicates that the structure containedin the powder corresponds to that determined in the single-crystal andthat this structure is unique, that is to say that there is no otherpolymorphic form mixed with form II of rimonabant.

Differential enthalpic analysis of the 2 crystalline forms was carriedout under the same conditions on an MDSC 2920 apparatus for differentialenthalpic analysis, marketed by TA Instruments SARL (PARIS); theprocedure is carried out under a nitrogen atmosphere, the initialtemperature is 30° C., it increases at the rate of 10° C./minute.

For each compound, the melting peak and the difference in enthalpy ofthe substance (ΔH) is measured before and after melting, in joules pergram of material.

Form I has a melting peak at 156±2° C. with ΔH=65±2 J/g.

Form II has a melting peak at 157±2° C. with ΔH=66±2 J/g.

Thus, the present invention relates to the crystalline polymorph ofrimonabant (form II), characterized by infrared spectrum absorptionbands as described in Table 2.

This polymorph is also characterized by the characteristic lines of theX-ray powder diffractogram as described in Table 4.

Furthermore, the crystalline polymorph is characterized by a meltingpeak at 157±2° C. with ΔH=66±2 J/g.

The solubility of the 2 crystalline forms of rimonabant in the samesolvent was also measured. The method used is described in Measurementof Solubility in J. W. Mullin. Crystallization: 3rd edition, Ipswich(GB): Butterworth—Heinemann, 1993, p. 105.

The measurements were carried out for each of the crystalline forms, insolution in methylcyclohexane at temperatures varying from 10° C. to 70°C. At equilibrium, for each temperature, the undissolved crystallineform is characterized by infrared spectrography, in particular by itsmain bands. The 2 trials carried out for each of the crystalline formsare presented in the table below: TABLE 6 Solubility Concentration ing/l Temperature ° C. Form I Form II 10.00 4.86 4.50 20.00 6.92 6.6030.00 9.30 9.20 40.00 13.70 12.60 50.00 20.40 19.00 60.00 31.20 29.2070.00 52.40 42.00

It is observed that rimonabant form II is less soluble at all thetemperatures between 10° C. and 70° C., this shows that rimonabant formII is thermodynamically more stable than rimonabant form I.

According to the present invention, the method for producing thecrystalline form II of rimonabant is characterized in that:

-   -   a) rimonabant is dissolved in the hot state in a solvent chosen        from:        -   methylcyclohexane in the pure state or containing 1 to 10%            of water by volume,        -   acetonitrile        -   4-methyl-2-pentanone,        -   acetone,    -   or a mixture of these solvents;    -   b) where appropriate, the medium is cooled to a temperature of        between 5° C. and 25° C.,    -   c) the crystals formed are filtered at a temperature of between        5° C. and 25° C.

According to a particular embodiment, which is the subject of thepresent invention, at the end of step a), the medium is inoculated withrimonabant having the crystalline form II.

The rimonabant which is dissolved in step a) is rimonabant in thecrystalline form I as obtained according to patent EP 0 656 354 orrimonabant form II or a mixture of the two forms. It is also possible toprepare rimonabant in crystalline form I directly from5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylicacid, according to the method described in EP 0 656 354; the acid isconverted to its acid chloride by the action of thionyl chloride, andthen 1-aminopiperidine is caused to react in the presence oftriethylamine.

The present invention has several particular embodiments.

One particular method is characterized in that:

-   -   a) rimonabant is dissolved at the concentration of 150 to 220        g/l by heating to the reflux temperature of a solvent consisting        of methylcyclohexane containing 1 to 10% of water, and then        either steps b), c) and d) below are carried out, or steps c)        and d) are carried out directly;    -   b) the medium is cooled to a temperature of between 40° C. and        50° C., and then the medium is heated to a temperature of        between 60° C. and 75° C. and maintained for 2 hours;    -   c) the temperature is reduced with a cooling step of −15° C. to        −20° C. per hour up to a temperature of between 5° C. and 20°        C.;    -   d) the crystals formed are filtered at a temperature of between        5° C. and 20° C.

Preferably, this method is characterized in that:

-   -   in step a), the compound is dissolved at the concentration of        200 g/l in a solvent consisting of methylcyclohexane containing        1 to 5% of water, by heating to the reflux temperature of the        solvent;    -   in step b), the medium is cooled to 45° C. over 30 minutes, and        then the medium is heated to 70° C.±2° C. and the temperature is        maintained for 2 hours;    -   in step c) the temperature is reduced with a step of −15° C. to        −20° C. per hour up to a temperature of between 15° C. and 20°        C.

According to one variant of the method according to the invention:

-   -   a) rimonabant is dissolved at the concentration of 50 to 250 g/l        in a solvent consisting of methylcyclohexane in the pure state        or containing 1 to 10% of water;    -   b) the medium is cooled to a temperature of between 65° C. and        75° C. and allowed to stand for 2 hours at this temperature;    -   c) the medium is inoculated by addition of 1% to 5% by weight of        rimonabant, crystalline form II;    -   d) the temperature is reduced with a cooling step of −15° C. to        −20° C. per hour up to a temperature of between 10° C. and 20°        C.;    -   e) the crystals formed are filtered at a temperature of between        10° C. and 20° C.

Preferably, this method is characterized in that:

-   -   in step a), rimonabant is at the concentration of 120 to 150        g/l;    -   in step b), the mixture is cooled to 70° C.;    -   in step c), the crystallization is initiated with 2% by weight        of rimonabant in crystalline form II.

According to another method of preparation:

-   -   a) rimonabant is dissolved at the concentration of 200 to 250        g/l while heating to the temperature of the solvent consisting        either of methylcyclohexane, or of methyl isobutyl ketone, or of        acetone, or of the mixture of these solvents;    -   b) the temperature is reduced with a cooling step of −10° C. to        −20° C. per hour until the nucleation begins, optionally the        nucleating temperature is maintained for 1 hour;    -   c) the temperature is again reduced with a cooling step of        −10° C. to −20° C. per hour until a temperature of between        10° C. and 20° C. is obtained;    -   d) the crystals are filtered at a temperature of between 10° C.        and 20° C.

Another embodiment of the method according to the invention ischaracterized in that:

-   -   a) rimonabant is dissolved at the concentration of 120 to 250        g/l by heating at the reflux temperature of the solvent which is        methylcyclohexane;    -   b) the mixture is cooled to a temperature of between 80° C. and        90° C.;    -   c) the medium is inoculated by adding 1% to 5% by weight of        rimonabant in crystalline form II in suspension in        methylcyclohexane and the temperature is maintained for one hour        between 80° C. and 90° C.;    -   d) the temperature is reduced with a cooling step of −15° C. to        −20° C. per hour up to a temperature of between 10° C. and 20°        C.;    -   e) the crystals formed are filtered at a temperature of between        10° C. and 20° C.

Preferably, this method is characterized in that:

-   -   in step a), rimonabant is dissolved at the concentration of 200        g/l in the solvent;    -   in step b), the mixture is cooled to 85° C.±2° C.;    -   in step c), the mixture is inoculated with 2% by weight of        rimonabant form II, and then the temperature of the medium is        maintained for one hour at 85° C.±2° C.

Another particular method of production according to the invention ischaracterized in that:

-   -   a) rimonabant is dissolved at room temperature in acetonitrile,        to saturation;    -   b) the mixture is left to evaporate at room temperature;    -   c) the crystals formed are recovered.

According to another embodiment, it is possible to use a solvent whichis not very polar, such as pure methylcyclohexane and to obtain therimonabant in form II using a seed crystal of rimonabant form II for thecrystallization.

This method of preparing the compound according to the invention ischaracterized in that:

-   -   a) rimonabant at the concentration of 150 g/l to 300 g/l in        methylcyclohexane is heated to a temperature of between 85° C.        and 95° C.;    -   b) the medium is inoculated with 1% to 5% by weight of        rimonabant in crystalline form II and the temperature is        maintained between 85° C. and 95° C. for several hours until        form I disappears;    -   c) the temperature is reduced with a cooling step of −10° C. to        −20° C. per hour up to a temperature of 10° C. to 20° C.;    -   d) the crystals formed are filtered at a temperature of between        10° C. and 20° C.

According to a particular embodiment, in step a), rimonabant is preparedat the concentration of 150 g/l to 300 g/l in methylcyclohexane bytreating5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylicacid chloride with 1-aminopiperidine in a mixture of methylcyclohexaneand tetrahydrofuran in the presence of triethylamine.

The crystalline form II of rimonabant has a stability greater than thatof form I described above. Furthermore, the crystalline form II ofrimonabant may be obtained in a specific manner by means of the methodof the invention; this constitutes an advantage for the industrialmanufacture of the crystalline form II of rimonabant.

Thus, the crystalline form II of rimonabant is particularly suitable forthe manufacture of pharmaceutical compositions useful for treating anydisease in which an antagonist of the CB₁ cannabinoid receptors isinvolved.

According to one of its aspects, the subject of the present invention ispharmaceutical compositions containing, as active ingredient, rimonabantin crystalline form II.

In the pharmaceutical compositions of the present invention foradministration by the oral, sublingual, subcutaneous, intramuscular,intravenous, transdermal or local route, the active ingredient, alone orin combination with another active ingredient, can be administered insingle-dose administration forms, as a mixture with conventionalpharmaceutical vehicles, to animals and human beings. The appropriatesingle-dose administration forms comprise the forms by the oral route,such as tablets, gelatin capsules, pills, powders, granules and oralsolutions or suspensions, sublingual and buccal administration forms,aerosols, implants, local, transdermal, subcutaneous, intramuscular,intravenous, intranasal or intraocular administration forms.

In the pharmaceutical compositions of the present invention, the activeingredient or active ingredients are generally formulated as dosageunits. The dosage unit contains 0.5 to 300 mg, advantageously from 5 to60 mg, preferably from 5 to 40 mg per dosage unit, for dailyadministrations, once or several times per day.

Although these dosages are examples of average situations, there may bespecific cases where higher or lower dosages are appropriate; suchdosages also form part of the invention. According to the usualpractice, the dosage appropriate for each patient is determined by thedoctor according to the method of administration and the age, the weightand the response of the said patient.

When a solid composition is prepared in the form of tablets or gelatincapsules, a mixture of pharmaceutical excipients is added to themicronized or nonmicronized active ingredients, which mixture can becomposed of diluents, such as, for example, lactose, mannitol,microcrystalline cellulose, starch or dicalcium phosphate, of binders,such as, for example, polyvinylpyrrolidone orhydroxypropylmethylcellulose, of disintegrating agents, such ascrosslinked polyvinylpyrrolidone or crosslinked carboxymethylcellulose,croscarmellose sodium, of flow agents, such as silica or talc, or oflubricants, such as magnesium stearate, stearic acid, glyceryltribehenate or sodium stearylfumarate.

Wetting agents or surfactants, such as sodium lauryl sulphate,polysorbate 80 or poloxamer 188, can be added to the formulation.

The tablets can be prepared by various techniques: direct tableting, drygranulation, wet granulation or hot-melt.

The tablets can be bare or sugar-coated (with sucrose, for example) orcoated with various polymers or other appropriate materials.

The tablets can have a flash, delayed or sustained release by preparingpolymeric matrices or by using specific polymers when forming the thinfilm.

The gelatin capsules may be soft or hard and may or may not be coatedwith a thin film, so as to have a flash, sustained or delayed activity(for example via an enteric form). They can comprise not only a solidformulation formulated as above for tablets but also liquids orsemi-solids.

A preparation in the form of a syrup or elixir can comprise the activeingredient or active ingredients in conjunction with a sweetener,preferably a calorie-free sweetener, methylparaben and propylparaben, asantiseptic, as well as a flavouring agent and an appropriate colorant.

The water-dispersible powders or granules can comprise the activeingredient or active ingredients as a mixture with dispersing agents,wetting agents or suspending agents, such as polyvinylpyrrolidone orpolyvidone, as well as with sweeteners or taste corrigents.

For rectal administration, recourse is had to suppositories which areprepared with binders which melt at the rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, use is made ofaqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which comprise pharmacologically compatible dispersing agentsand/or solubilizing agents, for example propylene glycol or butyleneglycol.

Thus, to prepare an aqueous solution which can be injected by theintravenous route, use may be made of a cosolvent, such as, for example,an alcohol, such as ethanol, or a glycol, such as polyethylene glycol orpropylene glycol, and of a hydrophilic surfactant, such as polysorbate80 or poloxamer 188. To prepare an oily solution which can be injectedby the intramuscular route, the active ingredient can be dissolved witha triglyceride or a glyceryl ester.

For local administration, use may be made of creams, ointments, gels,eyewashes or sprays.

For transdermal administration, use may be made of patches inmultilaminar or reservoir form, in which the active ingredient can be inalcoholic solution.

For administration by inhalation, use is made of an aerosol comprising,for example, sorbitan trioleate or oleic acid andtrichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane, freon substitutes or any other biologicallycompatible propellant gas; use may also be made of a system comprisingthe active ingredient, alone or in combination with an excipient, inpowder form.

The active ingredient or active ingredients can also be presented in theform of a complex with a cyclodextrin, for example α-, β- orγ-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

The active ingredient or active ingredients can also be formulated inthe form of microcapsules or microspheres, optionally with one or morevehicles or additives.

Use may be made of implants among the sustained-release forms of use inthe case of chronic treatments. These implants can be prepared in theform of an oily suspension or in the form of a suspension ofmicrospheres in an isotonic medium.

Preferably, rimonabant in crystalline form II is administered by theoral route, as a single dose per day.

According to another of its aspects, the invention also relates to amethod which consists in administering a therapeutically effectivequantity of rimonabant in crystalline form II.

EXAMPLE 1 Production of the Form II with No Seed Crystal inMethylcyclohexane Containing 1.64% Water

40 g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamideare solubilized, at room temperature, in 80 ml of tetrahydrofuran and240 ml of methylcyclohexane. The tetrahydrofuran is carried away bydistillation at atmospheric pressure. The heating is then interruptedand when the temperature is 80° C.±5° C., 4 ml of deionized water areadded. After cooling to 45° C.±3° C. and maintaining for at least 30minutes, the product crystallizes. The heterogeneous medium is thenheated again at 70° C.±2° C. for a period of at least 2 hours. Thecrystallization of the form II is completed by cooling to 20° C.±3° C.The crystals formed are filtered, washed with methylcyclohexane anddried under vacuum at 75° C.

In this trial, 38 g of form II of rimonabant are obtained.

EXAMPLE 2 Production of Form II in methylcyclohexane Containing 1.42%Water with 2% Seed Crystal of Form II

350 ml of methylcyclohexane and 5 ml of deionized water are added to 50g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.The reaction medium is heated to reflux temperature and then the heatingis interrupted. At 70° C.±3° C., the crystallization is initiated byaddition of 1 gram of substance of form II. The mixture is thus stirredfor 2 hours at 70° C. and then cooled to 20° C.±3° C. The crystalsformed are filtered, washed with methylcyclohexane and dried undervacuum at 75° C.

In this trial, 47.6 g of form II of rimonabant were obtained.

EXAMPLE 3 Production of Form II in Pure 4-methyl-2-pentanone

50 ml of 4-methyl-2-pentanone are added to 10 g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.

The reaction medium is heated to reflux temperature in order to obtainhomogenization and then cooled to 20° C.±3° C. The expected productcrystallizes. The crystals formed are filtered, washed with the minimumnecessary volume of 4-methyl-2-pentanone and dried under vacuum at 60°C.

In this trial, 4 g of form II of rimonabant were obtained.

EXAMPLE 4 Production of Form II in a 20% 4-methyl-2-pentanone and 80%methylcyclohexane Mixture

10 ml of 4-methyl-2-pentanone and 40 ml of methylcyclohexane are addedto 10 g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.

The reaction medium is heated to reflux temperature in order to obtainhomogenization. The heating is interrupted and the crystallization ofthe expected product is then observed at around 40° C. and then themixture is kept stirred at 20° C.±3° C. The crystals formed arefiltered, drained and dried under vacuum at 60° C.

In this trial, 7.9 grams of form II of rimonabant were obtained.

EXAMPLE 5 Production of Form II in a 60% 4-methyl-2-pentanone and 40%methylcyclohexane Mixture

30 ml of 4-methyl-2-pentanone and 20 ml of methylcyclohexane are addedto 10 g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.

The reaction medium is heated to reflux temperature; homogenization ofthe medium is thus obtained. The heating is then interrupted and thenthe mixture is cooled to 20° C.±3° C. The expected product crystallizes.The crystals formed are filtered, drained and then dried under vacuum at60° C.

In this trial, 4.8 g of form II of rimonabant were obtained.

EXAMPLE 6 Production of Form II in an 80% 4-methyl-2-pentanone and 20%methylcyclohexane Mixture

40 ml of methyl-4-pentanone and 10 ml of methylcyclohexane are added to10 g ofN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.

Homogenization of the reaction medium is obtained at the refluxtemperature of the solvent. The heating is then interrupted and themedium is allowed to return to 20° C.±3° C. The expected productcrystallizes. The crystals formed are filtered, drained and then driedunder vacuum at 60° C.

In this trial, 4 g of form II of rimonabant were obtained.

EXAMPLE 7 Production of Form II with 2% Seed Crystal of Form II from5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylicacid, in methylcyclohexane

A solution of 72.2 g of thionyl chloride in 60 ml of methylcyclohexaneis added, after heating to 83° C.±3° C., under a nitrogen atmosphere, toa suspension of 190.80 g of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylicacid in 940 ml of methylcyclohexane.

The mixture is stirred for 2 hours at 83° C.±3° C. and then thetemperature of the reaction medium is raised over 1 hour up to thereflux temperature of the methylcyclohexane while removing the excess ofthionyl chloride by distillation. The reaction medium is cooled to roomtemperature and a solution of 7 ml of triethylamine in 382 ml oftetrahydrofuran is added.

The solution obtained is added over 15 minutes at 12° C.±3° C. to amedium composed of 50.08 g of triethylamine, 55.10 g of1-aminopiperidine and 460 ml of methylcyclohexane. The temperature isallowed to rise to 20° C.±5° C. and then the organic phase issuccessively washed at 70° C.±3° C. with deionized water and acetic acidat 4% in water. The washes of the organic phase at 70° C.±3° C. arecompleted with a 1.5% NaOH solution and then with deionized water andthe tetrahydrofuran and the water are carried away by azeotropicdistillation at atmospheric pressure. The heating is then interruptedand when the temperature is 85° C., the crystallization of the expectedproducts is initiated by adding 4 g of substance of form II. The mixtureis thus stirred for 1 hour at 85° C.±3° C. and then cooled to 10° C.±3°C. over 5 hours and maintained for 2 hours at 10° C. The crystals formedare filtered, washed with methylcyclohexane, and dried under vacuum at60° C.

In this trial, 217 g of form II of rimonabant were obtained.

1. Crystalline polymorph of rimonabant (form II), characterized by theinfrared spectrum absorption bands described below: λ (cm⁻¹) λ (cm⁻¹)3311.30 1484.80 2787.23 986.57 1683.48 922.58 1526.55 781.02


2. Crystalline polymorph of rimonabant, characterized by the X-raypowder diffractogram lines described below: Peak Angle ångstroms2-Theta° d = 17.41664 5.070 d = 8.70963 10.148 d = 8.19062 10.793 d =5.82785 15.191 d = 4.63425 19.136 d = 3.49212 25.486


3. Crystalline polymorph of rimonabant, characterized by a melting peakat 157±2° C. with ΔH=66±2 J/g.
 4. Method for preparing the compoundaccording to any one of claims 1 to 3 wherein: a) rimonabant isdissolved in the hot state in a solvent chosen from: methylcyclohexanein the pure state or containing 1 to 10% of water by volume,acetonitrile 4-methyl-2-pentanone, acetone, or a mixture of thesesolvents; b) where appropriate, the medium is cooled to a temperature ofbetween 5° C. and 25° C., c) the crystals formed are filtered at atemperature of between 5° C. and 25° C.
 5. Method according to claim 4wherein after step a), the medium is inoculated with rimonabant,crystalline form II.
 6. Method according to claim 4 wherein a)rimonabant is dissolved at the concentration of 150 to 220 g/l byheating to the reflux temperature of a solvent consisting ofmethylcyclohexane containing 1 to 10% of water, and then either stepsb), c) and d) below are carried out, or steps c) and d) are carried outdirectly; b) the medium is cooled to a temperature of between 40° C. and50° C., and then the medium is heated to a temperature of between 60° C.and 75° C. and maintained for 2 hours; c) the temperature is reducedwith a cooling step of −15° C. to −20° C. per hour up to a temperatureof between 5° C. and 20° C.; d) the crystals formed are filtered at atemperature of between 5° C. and 20° C.
 7. Method according to claim 6wherein in step a), the compound is dissolved at the concentration of200 g/l in a solvent consisting of methylcyclohexane containing 1 to 5%of water, by heating to the reflux temperature of the solvent; in stepb), the medium is cooled to 45° C. over 30 minutes, and then the mediumis heated to 70° C.±2° C. and the temperature is maintained for 2 hours;in step c), the temperature is reduced with a step of −15° C. to −20° C.per hour up to a temperature of between 15° C. and 20° C.
 8. Methodaccording to claim 4 wherein a) rimonabant is dissolved at theconcentration of 50 to 250 g/l in a solvent consisting ofmethylcyclohexane in the pure state or containing 1 to 10% of water; b)the medium is cooled to a temperature of between 65° C. and 75° C. andallowed to stand for 2 hours at this temperature; c) the medium isinoculated by addition of 1% to 5% by weight of rimonabant, crystallineform II; d) the temperature is reduced with a cooling step of −15° C. to−20° C. per hour up to a temperature of between 10° C. and 20° C.; e)the crystals formed are filtered at a temperature of between 10° C. and20° C.
 9. Method according to claim 8 wherein in step a), rimonabant isat the concentration of 120 to 150 μl; in step b), the mixture is cooledto 70° C.; in step c), the crystallization is initiated with 2% byweight of rimonabant in crystalline form II.
 10. Method according toclaim 4 wherein a) rimonabant is dissolved at the concentration of 200to 250 g/l while heating to the temperature of the solvent consistingeither of methylcyclohexane, or of methyl isobutyl ketone, or ofacetone, or of the mixture of these solvents; b) the temperature isreduced with a cooling step of −10° C. to −20° C. per hour until thenucleation begins, optionally the nucleating temperature is maintainedfor 1 hour; c) the temperature is again reduced with a cooling step of—I 0° C. to −20° C. per hour until a temperature of between 10° C. and20° C. is obtained; d) the crystals are filtered at a temperature ofbetween 10° C. and 20° C.
 11. Method according to claim 4 wherein a)rimonabant is dissolved at the concentration of 120 to 250 g/l byheating at the reflux temperature of the solvent which ismethylcyclohexane; b) the mixture is cooled to a temperature of between80° C. and 90° C.; c) the medium is inoculated by adding 1% to 5% byweight of rimonabant in crystalline form II in suspension inmethylcyclohexane and the temperature is maintained for one hour between80° C. and 90° C.; d) the temperature is reduced with a cooling step of−15° C. to −20° C. per hour up to a temperature of between 10° C. and20° C.; e) the crystals formed are filtered at a temperature of between10° C. and 20° C.
 12. Method according to claim 11 wherein in step a),rimonabant is dissolved at the concentration of 200 g/l in the solvent;in step b), the mixture is cooled to 85° C.±2° C.; in step c), themixture is inoculated with 2% by weight of rimonabant form II, and thenthe temperature of the medium is maintained for one hour at 85° C.±2° C.13. Method according to claim 4 wherein a) rimonabant is dissolved atroom temperature in acetonitrile, to saturation; b) the mixture is leftto evaporate at room temperature; c) the crystals formed are recovered.14. Method for prepareng the compound according to any one of claims 1to 3 wherein a) rimonabant at the concentration of 150 g/l to 300 g/l inmethylcyclohexane is heated to a temperature of between 85° C. and 95°C.; b) the medium is inoculated with 1% to 5% by weight of rimonabant incrystalline form II and the temperature is maintained between 85° C. and95° C. for several hours until form I disappears; c) the temperature isreduced with a cooling step of −15° C. to −20° C. per hour up to atemperature of between 10° C. and 20° C.; d) the crystals formed arefiltered at a temperature of between 10° C. and 20° C.
 15. Methodaccording to claim 14 wherein in step a), rimonabant is prepared at theconcentration of 150 μl to 300 μl in methylcyclohexane by treating5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylicacid chloride in methylcyclohexane with 1-aminopiperidine in a mixtureof methylcyclohexane and tetrahydrofuran in the presence oftriethylamine.
 16. Pharmaceutical composition containing, as activeingredient, the crystalline polymorph of rimonabant (form II) accordingto claim 1 in combination with at least one pharmaceutical excipient.17. A method for treating diseases in which an antagonist of the CB₁cannabinoid receptor is involved which comprises administering to apatient in need of such treatment an effective amount of a compoundaccording to claim
 1. 18. A method for treating diseases in which anantagonist of the CB₁ cannabinoid receptor is involved which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 2. 19. A method for treating diseasesin which an antagonist of the CB₁ cannabinoid receptor is involved whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 3. 20. Pharmaceuticalcomposition containing, as active ingredient, the crystalline polymorphof rimonabant (form II) according to claim 2 in combination with atleast one pharmaceutical excipient.
 21. Pharmaceutical compositioncontaining, as active ingredient, the crystalline polymorph ofrimonabant (form II) according to claim 3 in combination with at leastone pharmaceutical excipient.